Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2596616 | Toxicology | 2009 | 10 Pages |
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a known disruptor of B-cell differentiation and a ligand for the aryl hydrocarbon receptor (AhR), induces binding of the AhR to dioxin responsive elements (DRE) in sensitive genes. The Ig heavy chain (IgH) gene is a sensitive target of TCDD and may be transcriptionally inhibited by TCDD through inhibition of the 3â²IgH transcriptional regulatory region (3â²IgHRR). While the 3â²IgHRR contains binding sites for several transcription factors, two DRE motifs were also identified which may be responsible for TCDD-induced inhibition of 3â²IgHRR activation and may implicate the AhR as an important regulator of IgH expression. The objectives of the present study were to determine if 3â²IgHRR modulation is limited to TCDD or if structurally diverse chemicals (AhR ligands and non-AhR ligands) from environmental, industrial, dietary or pharmaceutical origin are also capable of modulating the 3â²IgHRR and to verify a correlation between effects on a stable 3â²IgHRR reporter and the endogenous IgH protein. Utilizing a CH12.LX mouse B-cell line that stably expresses a 3â²IgHRR-regulated transgene, we identified an inhibition of both 3â²IgHRR activation and IgH protein expression by the non-dioxin AhR activators indolo(3,2-b)carbazole, primaquine, carbaryl, and omeprazole which followed a rank order potency for AhR activation supporting a role of the AhR in the transcriptional regulation of the 3â²IgHRR and IgH expression. However, modulation of the 3â²IgHRR and IgH expression was not limited to AhR activators or to suppressive effects. Hydrogen peroxide and terbutaline had an activating effect and benzyl isothiocyanate was inhibitory. These chemicals are not known to influence the AhR signaling pathway but have been previously shown to modulate humoral immunity and/or transcription factors that regulate the 3â²IgHRR. Taken together these results implicate the 3â²IgHRR as a sensitive immunological target and are the first to identify altered 3â²IgHRR activation by a diverse range of chemicals.
Keywords
HAHsARNTDRERT-PCRIgHIC50TCDDICZAP-1BITCLPSAHRNF-1PBSNF-κB2,3,7,8-Tetrachlorodibenzo-p-dioxin50% inhibitory concentrationDMSOOctimmunoglobulin Benzyl isothiocyanateELISAEnzyme-linked immunosorbent assayIn vitroDimethyl sulfoxideImmunoglobulin heavy chainvariable heavy chaindioxin responsive elementnuclear factor-κBAhR nuclear translocatorPhosphate buffered salinelipopolysaccharideneurofibromatosis type 1Polycyclic aromatic hydrocarbonsPAHsHalogenated aromatic hydrocarbonsreverse transcription-polymerase chain reactionactivator protein 1aryl hydrocarbon receptor
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Authors
Rebecca A. Henseler, Eric J. Romer, Courtney E.W. Sulentic,